Note: Descriptions are shown in the official language in which they were submitted.
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Description
Title of Invention: MEDICAMENT
Technical Field
[0001]
The present invention relates to a medicament for
preventing or treating pulmonary hypertension.
Background Art
[0002]
Pulmonary hypertension is an increase of pulmonary
artery pressure caused by abnormal proliferation,
remodeling, contraction, etc., of myocardial or pulmonary
vascular tissues, which is accompanied by right heart
failure with the progression of the disease, leading to
death. This disease has a very poor prognosis. Main
therapeutic drugs currently used are endothelin receptor
antagonists, phosphodiesterase 5 inhibitors, prostacyclin
analogs, soluble guanylate cyclase (sGC) stimulators, and
the like. Although these therapeutic drugs ameliorate
some of symptoms, the prognosis of the disease is still
poor. In recent years, a plurality of molecules have
been found to participate in the pathological condition
of the disease. In addition, the existing therapeutic
drugs are limited by their effects when used alone.
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Therefore, the development of a novel therapeutic drug
has been demanded.
[0003]
A calcium-sensing receptor (CaSR) is a G protein-
coupled receptor (GPCR) that senses change in
extracellular calcium concentration, and is known to be
associated with various diseases. Recent reports state
that: CaSR is overexpressed in pulmonary artery smooth
muscle cells (PASMCs) isolated from pulmonary
hypertension patients; and the enhanced functions of CaSR
cause abnormal proliferation of pulmonary vascular
tissues, etc. In monocrotaline (MCT)-induced pulmonary
hypertensive rats and hypoxia-induced pulmonary
hypertensive (HPH) mice, a compound NPS-2143 having an
effect as a CaSR antagonist has been reported to inhibit
cardiac hypertrophy, a rise in right ventricular systolic
pressure, myocardial tissue fibrosis, and pulmonary
vascular remodeling, etc. (Non Patent Literatures 1 to 5).
Also, NPS-2143 and Calhex 231 (negative allosteric
modulators) have been reported to enhance the effect of
an existing pulmonary arterial hypertension (PAH) drug
(PDE 5 inhibitor/sildenafil) (Non Patent Literature 7),
and there is a report on the action of CaSR on vascular
tone, cardiovascular blood pressure, and pulmonary
hypertension using CaSR knockout mice (Non Patent
Literatures 8 to 9). However, the medical needs of
therapeutic drugs for pulmonary hypertension are still
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high. Thus, there has been a demand for the development
of a medicament for preventing or treating pulmonary
hypertension, having excellent properties in terms of
drug efficacy, specificity, and low toxicity.
[0004]
(5R)-N-[1-Ethy1-1-(4-ethylphenyl)propy1]-2,7,7-
trimethy1-5-pheny1-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrimidine-3-carboxamide (hereinafter, also referred to
as "compound A"), (5R)-N-[1-ethy1-1-(4-
methoxyphenyl)propy1]-2,7,7-trimethyl-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide
(hereinafter, also referred to as "compound B"), and
(5R)-N-[1-ethy1-1-(4-ethylphenyl)propy1]-5-(2-
fluoropheny1)-2,7,7-trimethy1-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide
(hereinafter, also referred to as "compound C") are known
to participate in the activity modulation of a calcium-
sensing receptor (CaSR) and to participate in the
regulation of parathyroid hormone (PTH) (Patent
Literatures 1 and 2). Non Patent Literature 6 discloses
that tosylate of compound A is a CaSR antagonist.
Citation List
Patent Literature
[0005]
Patent Literature 1: W02004/017908
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Patent Literature 2: Japanese Patent Laid-Open No. 2005-
239611
Non Patent Literature
[0006]
Non Patent Literature 1: Circ. Res., 111 (4): 469-481,
2012
Non Patent Literature 2: Circ. Res., 112 (4): 640-650,
2013
Non Patent Literature 3: YAKUGAKU ZASSHI, 133 (12): 1351-
1359, 2013
Non Patent Literature 4: J. Smooth Muscle Res., 50: 8-17,
2014
Non Patent Literature 5: Hypertens Res., 37 (2): 116-124,
2014
Non Patent Literature 6: Bioorganic & Medicinal Chemistry
19: 1881-1894, 2011
Non Patent Literature 7: Eur. J. Pharmacol. 784: 15-21,
2016
Non Patent Literature 8: Am. J. Physiol. Lung Cell Mol.
Physiol. 310: 846-859, 2016
Non Patent Literature 9: Am. J. Physiol. Cell Physiol.
310: 193-204, 2016
Summary of Invention
Technical Problem
[0007]
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The present invention provides a medicament for
preventing or treating pulmonary hypertension.
Solution to Problem
[0008]
The present inventors have found that a compound
selected from the group consisting of compound A,
compound B, compound C, and the salt thereof is effective
for preventing or treating pulmonary hypertension. The
present invention has been made on the basis of this
finding.
[0009]
Specifically, the present invention provides the
following aspects:
[1] A medicament for preventing or treating pulmonary
hypertension, comprising a compound selected from the
group consisting of (5R)-N-[1-ethy1-1-(4-
ethylphenyl)propy1]-2,7,7-trimethyl-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-alpyrimidine-3-carboxamide, (5R)-
N-[1-ethy1-1-(4-methoxyphenyl)propy1]-2,7,7-trimethy1-5-
pheny1-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-
carboxamide, (5R)-N-[1-ethy1-1-(4-ethylphenyl)propy1]-5-
(2-fluoropheny1)-2,7,7-trimethyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, and
the salt thereof.
[2] The medicament according to [1], wherein the
pulmonary hypertension is pulmonary arterial hypertension.
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[3] A method of preventing or treating pulmonary
hypertension in a mammal, comprising administering to the
mammal a compound selected from the group consisting of
(5R)-N-[1-ethy1-1-(4-ethylphenyl)propy1]-2,7,7-trimethyl-
5-pheny1-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-
carboxamide, (5R)-N-[1-ethy1-1-(4-methoxyphenyl)propy1]-
2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrimidine-3-carboxamide, (5R)-N-[1-ethy1-1-(4-
ethylphenyl)propy1]-5-(2-fluoropheny1)-2,7,7-trimethyl-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide,
and the salt thereof.
[4] The method according to [3], wherein the pulmonary
hypertension is pulmonary arterial hypertension.
[5] A compound selected from the group consisting of
(5R)-N-[1-ethy1-1-(4-ethylphenyl)propy1]-2,7,7-trimethyl-
5-pheny1-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-
carboxamide, (5R)-N-[1-ethy1-1-(4-methoxyphenyl)propy1]-
2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrimidine-3-carboxamide, (5R)-N-[1-ethy1-1-(4-
ethylphenyl)propy1]-5-(2-fluoropheny1)-2,7,7-trimethyl-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide,
and the salt thereof, for preventing or treating
pulmonary hypertension.
[6] The compound according to [5], wherein the pulmonary
hypertension is pulmonary arterial hypertension.
[7] Use of a compound selected from the group consisting
of (5R)-N-[1-ethy1-1-(4-ethylphenyl)propy1]-2,7,7-
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trimethy1-5-pheny1-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrimidine-3-carboxamide, (5R)-N-[1-ethy1-1-(4-
methoxyphenyl)propy1]-2,7,7-trimethyl-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, (5R)-
N-(1-ethy1-1-(4-ethylphenyl)propy1]-5-(2-fluoropheny1)-
2,7,7-trimethy1-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrimidine-3-carboxamide, and the salt thereof for
manufacturing a preventive or treatment agent for
pulmonary hypertension.
[8] The use according to [7], wherein the pulmonary
hypertension is pulmonary arterial hypertension.
Advantageous Effects of Invention
[0010]
According to the present invention, pulmonary
hypertension can be prevented or treated. The medicament
of the present invention can be orally administered, and
when orally administered, produces fewer adverse
reactions (e.g., infection) as compared with a medicament
for non-oral administration. The medicament of the
present invention is expected to have an excellent
therapeutic effect and prognosis-improving effect on
pulmonary hypertension, and furthermore, is
advantageously easily handled by patients, healthcare
professionals, and persons involved.
Brief Description of Drawing
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[0011]
[Figure 1] Figure 1 shows a Kaplan-Meier survival curve
of each administration group in monocrotaline-induced
pulmonary hypertensive rat models.
Description of Embodiments
[0012]
In the present specification, the term "subject"
refers to a mammal, for example, a human. In the present
specification, the "subject having pulmonary
hypertension" means a subject affected by pulmonary
hypertension. When the subject is a human, the subject
is called a "patient". When the subject affected by
pulmonary hypertension is a human, the subject is called
a "pulmonary hypertension patient".
[0013]
In the present specification, the term
"pharmaceutically acceptable salt" means an acid-addition
salt or a base-addition salt that is acceptable for
administration to organisms.
[0014]
In the present specification, the term
"therapeutically effective amount" means an amount which
results in a therapeutic effect on the subject, and means,
for example, that in the subject who has received the
amount, the symptom of the disease or condition is
alleviated, mitigated, or the development of the symptom
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of the disease or condition is delayed or inhibited
compared with a subject who has not received the amount.
A therapeutically effective amount can be appropriately
determined by doctors in view of the age, weight, sex and
the severity of the disease of the subject.
[0015]
In the present specification, the term "pulmonary
hypertension" means a condition in which pulmonary artery
pressure is increased. General "hypertension" means a
condition in which the pressure within a vascular vessel
of blood sent from the left ventricle through the aorta
into the body is elevated. By contrast, the "pulmonary
hypertension" is a condition in which the pulmonary
artery from the right ventricle to the lung has high
blood pressure. The pulmonary hypertension occurs
independently of the general hypertension. The normal
values of pulmonary artery pressure at rest are a
systolic pressure of approximately 20 mmHg to
approximately 30 mmHg, a diastolic pressure of
approximately 7 mmHg to approximately 12 mmHg, and a mean
pressure of approximately 10 mmHg to approximately 15
mmHg in the human lung.
[0016]
Diagnostic criteria for pulmonary hypertension are
described in, for example, the Guidelines for treatment
of pulmonary hypertension (2012, revised) provided by The
Japanese Circulation Society.
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The diagnosis of pulmonary hypertension in humans is
usually conducted on the basis of mean pulmonary artery
pressure (mean PAP) actually measured by right heart
catheterization at rest. A subject having a mean
pulmonary artery pressure of 25 mmHg or higher can be
diagnosed as having pulmonary hypertension. Recent
advances of echocardiography allow pulmonary artery
pressure to be estimated in a non-invasive manner. The
diagnosis of pulmonary hypertension is also conducted on
the basis of the estimated value of pulmonary artery
pressure.
[0017]
The pulmonary hypertension is clinically classified
according to the Dana Point classification into five
groups: group 1 to group 5. Group 1 is pulmonary
arterial hypertension (PAH); group 2 is pulmonary
hypertension owing to left ventricular cardiac disease;
group 3 is pulmonary hypertension owing to lung diseases
and/or hypoxia; group 4 is chronic thromboembolic
pulmonary hypertension; and group 5 is pulmonary
hypertension with unclear multifactorial mechanisms.
Group l' (pulmonary veno-occlusive disease and/or
pulmonary capillary hemangiomatosis) and group 1"
(persistent pulmonary hypertension of the newborn) are
also known as subgroups of group 1.
[0018]
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The pulmonary arterial hypertension of group 1 is
the most typical pulmonary hypertension and is broadly
divided into idiopathic PAH, heritable PAH, drug- and
toxin-induced PAH, and PAH owing to each disease.
[0019]
In the present invention, various symptoms
associated with pulmonary hypertension (e.g., elevated
right ventricular pressure) can be improved (for example,
pulmonary artery pressure in a subject can be lowered) by
the administration of a compound selected from the group
consisting of compounds A, B, and C, and the salt thereof
to the subject.
[0020]
Thus, the present invention provides a medicament
for preventing or treating pulmonary hypertension,
comprising a compound selected from compounds A, B, and C,
and the salt thereof.
[0021]
Compound A is represented by the following formula:
[Formula 1]
HNe= =õ
1111
0
[0022]
Compound B is represented by the following formula:
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[Formula 2]
N-KX
/ "
H N 110
0
0
[0023]
Compound C is represented by the following formula:
[Formula 3]
N
H N =
1111 1111
0
[0024]
In a particular aspect of the present invention, the
medicament of the present invention can be used in the
prevention or treatment of pulmonary hypertension
selected from the following pulmonary hypertensions:
pulmonary artery hypertension; pulmonary hypertension
caused by pulmonary veno-occlusive disease, and pulmonary
hypertension caused by pulmonary capillary
hemangiomatosis; persistent pulmonary hypertension of the
newborn; pulmonary hypertension accompanied by left
ventricular systolic dysfunction, left ventricular
diastolic dysfunction, valvular disease, or congenital or
acquired left ventricular inflow or outflow tract
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obstruction; pulmonary hypertension caused by chronic
obstructive lung disease, interstitial lung disease,
other lung diseases accompanied by mixed restrictive and
obstructive disorder, sleep-disordered breathing,
alveolar hypoventilation syndrome, chronic exposure to
high altitude, or disturbance of development; chronic
thromboembolic pulmonary hypertension; and pulmonary
hypertension accompanied by hematologic disorders
(chronic hemolytic anemia, myeloproliferative disease, or
splenectomy), systemic disorders (sarcoidosis, pulmonary
Langerhans' cell histiocytosis, lymphangioleiomyomatosis,
neurofibromatosis, or vasculitis), metabolic disorders
(glycogenosis, Gaucher's disease, or thyroid gland
disease), or other vascular compressions of the lung
(tumor embolism, fibrous mediastinitis, or chronic renal
failure). The medicament of the present invention can
preferably be used in the prevention or treatment of
pulmonary arterial hypertension.
[0025]
Compound A, B, or C, or the salt thereof may be a
non-solvate or may be a solvate. The solvate can be
formed in a solvent such as ethanol or water. The
solvate whose solvent is water is a hydrate. The hydrate
encompasses stoichiometric hydrates as well as hydrates
containing various amounts of water.
[0026]
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Compound A, B, or C, or the salt thereof may be
labeled with an isotope (e.g., 3H, 13C, 14C, 18F, 385, and
1251) or the like.
A deuterium conversion form having 2H(D) converted
from IH is also included in compound A, B, or C, or the
salt thereof.
[0027]
Examples of the salt of compound A, B, or C include
salts with inorganic bases, ammonium salts, salts with
organic bases, salts with inorganic acids, salts with
organic acids, and salts with basic or acidic amino acids.
Preferred examples of the salts with inorganic bases
include: alkali metal salts such as sodium salt and
potassium salt; alkaline earth metal salts such as
calcium salt, magnesium salt, and barium salt; and
aluminum salts.
Preferred examples of the salts with organic bases
include salts with trimethylamine, triethylamine,
pyridine, picoline, ethanolamine, diethanolamine,
triethanolamine, dicyclohexylamine, and N,N'-
dibenzylethylenediamine.
Preferred examples of the salts with inorganic acids
include salts with hydrochloric acid, hydrobromic acid,
nitric acid, sulfuric acid, and phosphoric acid.
Preferred examples of the salts with organic acids
include salts with formic acid, acetic acid,
trifluoroacetic acid, fumaric acid, oxalic acid, tartaric
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acid, maleic acid, citric acid, succinic acid, malic acid,
methanesulfonic acid, benzenesulfonic acid, and p-
toluenesulfonic acid.
Preferred examples of the salts with basic amino
acids include salts with arginine, lysine, and ornithine.
Preferred examples of the salts with acidic amino
acids include salts with aspartic acid and glutamic acid.
Among these salts, a pharmaceutically acceptable
salt is preferred.
[0028]
In a particular aspect of the present invention, the
salt of compound A can be p-toluenesulfonate (tosylate)
(hereinafter, also referred to as "compound A'"). In a
particular aspect of the present invention, the salt of
compound B can be hydrochloride (hereinafter, also
referred to as "compound B'"). In a particular aspect of
the present invention, the salt of compound C can be p-
toluenesulfonate (tosylate) (hereinafter, also referred
to as "compound C'").
[0029]
In a particular aspect of the present invention, a
compound selected from compound A, compound A', compound
B, compound B', compound C, and compound C' can be used
in the prevention or treatment of pulmonary hypertension.
Thus, the present invention provides a medicament for
preventing or treating pulmonary hypertension, comprising
a compound selected from compound A, compound A',
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compound B, compound B', compound C, and compound C'. In
this particular aspect, the pulmonary hypertension can be
pulmonary arterial hypertension.
In a particular aspect of the present invention,
compound A or compound A' can be used in the prevention
or treatment of pulmonary hypertension. Thus, the
present invention provides a medicament for preventing or
treating pulmonary hypertension, comprising compound A or
compound A'. In this particular aspect, the pulmonary
hypertension can be pulmonary arterial hypertension.
In a particular aspect of the present invention,
compound A' can be used in the prevention or treatment of
pulmonary hypertension. Thus, the present invention
provides a medicament for preventing or treating
pulmonary hypertension, comprising compound A'. In this
particular aspect, the pulmonary hypertension can be
pulmonary arterial hypertension.
[0030]
In a particular aspect of the present invention, the
present invention further provides a medicament for
improving one or more conditions selected from the group
consisting of right ventricular pressure, right
ventricular systolic pressure, a survival rate, and
cardiac hypertrophy in a subject having pulmonary
hypertension, comprising a compound selected form
compounds A, B, and C, and the salt thereof.
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In a particular aspect of the present invention, the
present invention provides a medicament for improving one
or more conditions selected from the group consisting of
right ventricular pressure, right ventricular systolic
pressure, a survival rate, and cardiomegaly in a subject
having pulmonary hypertension, comprising compound A or a
salt of compound A.
In a particular aspect of the present invention, the
present invention provides a medicament for improving one
or more conditions selected from the group consisting of
right ventricular pressure, right ventricular systolic
pressure, a survival rate, and cardiomegaly in a subject
having pulmonary hypertension, comprising compound A'.
[0031]
Compounds A, B, and C, and the salt thereof can be
prepared by a method known per se in the art (e.g., a
method described in W02004/017908 and Yoshida M. et al.,
Bioorg. Med. Chem., 19: 1881-1894, 2011).
[0032]
The dose differs depending on a recipient subject,
an administration route, a disease, symptoms, etc. In
the case of, for example, oral administration to a human
(body weight: approximately 50 kg), the dose can be
selected from the range of approximately 0.1 mg to
approximately 500 mg, preferably the range of
approximately 1 mg to approximately 100 mg, in terms of
the amount of compound A, B, or C. In the case of non-
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oral administration to a human (body weight:
approximately 50 kg), the dose can be selected from the
range of approximately 0.01 mg to approximately 100 mg,
preferably the range of approximately 0.1 mg to
approximately 10 mg, in terms of the amount of compound A,
B, or C. This amount can be administered in one portion
to several divided portions per day (e.g., one portion to
three portions per day).
[0033]
The medicament of the present invention may contain
a pharmaceutically acceptable carrier in addition to the
compound selected from compounds A, B, and C, and the
salt thereof.
Any of various organic or inorganic carrier
materials routinely used as pharmaceutical materials may
be used as the pharmaceutically acceptable carrier and
may be mixed as excipients, lubricants, binding agents,
and disintegrants for solid preparations; and solvents,
solubilizing agents, suspending agents, isotonic agents,
buffering agents, and soothing agents for liquid
preparations. If necessary, pharmaceutical additives
such as preservatives, antioxidants, stabilizers,
colorants, and sweeteners can also be used.
[0034]
In a certain aspect, the medicament of the present
invention can be a medicament for parenteral
administration or for oral administration. The
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medicament of the present invention can also be a
medicament for oral administration.
[0035]
The medicament of the present invention can be used
in combination with a drug such as a different
therapeutic drug for pulmonary hypertension and can be
used in combination with, for example, any of the
following drugs:
(1) Endothelin receptor antagonists
Endothelin receptor antagonists such as macitentan,
bosentan, and ambrisentan
(2) Prostaglandin preparations
Prostaglandin preparations (or prostacyclin
preparations) such as epoprostenol, beraprost,
treprostinil, iloprost, and selexipag
(3) Phosphodiesterase-5 inhibitors
Phosphodiesterase-5 inhibitors such as sildenafil
and tadalafil
(4) Soluble adenylate cyclase stimulators
Soluble adenylate cyclase stimulators such as
riociguat
(5) Calcium channel blockers
Calcium channel blockers such as nifedipine,
diltiazem, and amlodipine
(6) Rho kinase inhibitors
Rho kinase inhibitors such as fasudil
(7) Others
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Tyrosine kinase inhibitors such as imatinib and
sorafenib; anticoagulants such as warfarin and aspirin;
diuretics such as furosemide and spironolactone;
cardiotonics such as dopamine and digoxin; etc.
[0036]
The medicament mixed with or used in combination
with the medicament of the present invention includes all
of a medicament formulated as a single preparation
containing the compound selected from compounds A, B, and
C, and the salt thereof and the concomitant drug; and
separate preparations of the compound selected from
compounds A, B, and C, and the salt thereof and the
concomitant drug. Hereinafter, these preparations are
collectively referred to as the combined use agent of the
present invention.
[0037]
The combined use agent of the present invention can
be prepared by separately or simultaneously formulating
the compound selected from compounds A, B, and C, and the
salt thereof and the concomitant drug, either directly or
after mixing with a pharmaceutically acceptable carrier,
etc., in the same way as in the aforementioned medicament
comprising the compound selected from compounds A, B, and
C, and the salt thereof. The daily dose of the combined
use agent of the present invention differs depending on
severity of the condition; the age, sex, body weight, and
difference in sensitivity of a recipient subject; the
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time of administration and dosing intervals; the
properties, prescription, or type of the medicament; the
type of the active ingredient, etc., and is not
particularly limited.
[0038]
For the administration of the combined use agent of
the present invention, the compound selected from
compounds A, B, and C, and the salt thereof and the
concomitant drug may be administered at the same time.
Alternatively, the concomitant drug may be first
administered, followed by the administration of the
compound selected from compounds A, B, and C, and the
salt thereof, or the compound selected from compounds A,
B, and C, and the salt thereof may be first administered,
followed by the administration of the concomitant drug.
In the case of administering the compound and the
concomitant drug in the staggered manner, the time
interval differs depending on the active ingredient to be
administered, the dosage form, and the administration
method. Examples of the method for first administering
the concomitant drug include a method which involves
administering the concomitant drug and administering the
compound selected from compounds A, B, and C, and the
salt thereof within 1 minute to 3 days, preferably within
minutes to I day, more preferably within 15 minutes to
1 hour thereafter. Examples of the method for first
administering the compound selected from compounds A, B,
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and C, and the salt thereof include a method which
involves administering the compound and administering the
concomitant drug within 1 minute to I day, preferably
within 10 minutes to 6 hours, more preferably within 15
minutes to 1 hour thereafter.
[0039]
The respective amounts of the compound selected from
compounds A, B, and C, and the salt thereof and the
concomitant drug in the combined use agent of the present
invention containing the compound selected from compounds
A, B, and C, and the salt thereof and the concomitant
drug in a single preparation differ depending on the form
of the preparation and are usually approximately 0.01 to
90% by weight, preferably approximately 0.1 to 50% by
weight, more preferably approximately 0.5 to 20% by
weight, with respect to the total weight of the
preparation.
[0040]
The content of the carrier in the combined use agent
is usually approximately 0 to 99.8% by weight, preferably
approximately 10 to 99.8% by weight, more preferably
approximately 10 to 90% by weight, with respect to the
total weight of the preparation.
[0041]
When the combined use agent of the present invention
comprises separate medicaments respectively containing
the compound selected from compounds A, B, and C, and the
,
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salt thereof and the concomitant drug, the combined use
agent containing the concomitant drug can be produced in
the same way as in the combined use agent comprising the
compound selected from compounds A, B, and C, and the
salt thereof.
[0042]
The medicament of the present invention may be any
of solid preparations including powders, granules,
tablets, and capsules, and liquid preparations including
syrups and emulsions.
The medicament of the present invention can be
produced by a routine method, for example, mixing,
kneading, granulation, tableting, coating, sterilization,
and/or emulsification, according to the form of the
preparation. For such pharmaceutical production, see,
for example, each section of the Japanese Pharmacopoeia
(16th edition) General Rules for Preparations. The
medicament of the present invention may be prepared into
a sustained-release agent containing the active
ingredient and a biodegradable polymer compound.
[0043]
In a certain aspect of the present invention, the
present invention provides a medicament for preventing or
treating pulmonary hypertension in a subject in need
thereof, comprising a compound selected from compounds A,
B, and C, and the salt thereof, wherein the compound is
used in combination with a concomitant drug.
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[0044]
In an alternative aspect of the present invention,
the present invention provides a method for preventing or
treating pulmonary hypertension in a subject in need
thereof, comprising administering a compound selected
from compounds A, B, and C, and the salt thereof to the
subject. In the method of the present invention, the
pulmonary hypertension to be treated can be any of the
diseases and the conditions described as the subject to
be treated as to the medicament of the present invention.
In the present method, a therapeutically effective amount
of said compound can be administered to the subject. In
the case of administering the compound selected from
compounds A, B, and C, and the salt thereof in the method
of the present invention, a medicament comprising the
compound selected from compounds A, B, and C, and the
salt thereof may be administered.
[0045]
In a further alternative aspect of the present
invention, the present invention provides use of a
compound selected from compounds A, B, and C, and the
salt thereof for producing or in the manufacture of a
medicament for preventing or treating pulmonary
hypertension in a subject in need thereof. The pulmonary
hypertension to be treated with the medicament can be any
of the diseases and the conditions described as the
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subject to be treated as to the medicament of the present
invention.
[0046]
In a further aspect of the present invention, the
present invention provides a compound selected from the
group consisting of compounds A, B, and C, and the salt
thereof for use in preventing or treating pulmonary
hypertension in a subject in need thereof. The pulmonary
hypertension to be treated with the medicament can be any
of the diseases and the conditions described as the
subject to be treated as to the medicament of the present
invention.
[0047]
In a certain aspect of the present invention, the
compound contained in the compound or the medicament to
be administered is tosylate salt of compound A.
Examples
[0048]
Compound A' was prepared by the known method
described in W02004/017908 and Yoshida M. et al., Bioorg.
Med. Chem., 19: 1881-1894, 2011.
[0049]
Example 1: Therapeutic effect of compound A' on pulmonary
hypertension in pulmonary hypertensive animal model
(right ventricular pressure, right ventricular systolic
CA 03019091 2018-09-26
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pressure, right ventricular hypertrophy, pulmonary artery
medial wall thickening, pulmonary artery occlusion)
[0050]
(1) Experimental method
Monocrotaline (MCT) was subcutaneously injected at
50 mg/kg (in 50% dimethyl sulfoxide solution) to male
Sprague-Dawley rats having a body weight of 250 g 10%
to prepare pulmonary hypertensive rat models. Compound
A' and the same amount of a vehicle were orally
administered to a compound A' administration group (dose:
1 mg/kg, 3 mg/kg, or 10 mg/kg) and a control group,
respectively, every day over 14 days from the 14th day
after the MCT administration. This experiment was
carried out using these groups each involving 9 rats (12
rats were used only in a vehicle control group).
[0051]
(2) Effect on right ventricular pressure (RVP)
The right ventricular pressure (RVP) was measured by
catheterization for the rats that survived at 28 days
after MCT administration (negative control group
(monocrotaline non-administered group), 9 rats; vehicle
control group, 8 rats; compound A' 1 mg/kg administration
group, 9 rats; compound A' 3 mg/kg administration group,
rats; compound A' 10 mg/kg administration group, 9
rats; total 40 rats). The results are shown in Table 1.
[0052]
[Table 1]
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Effect on right ventricular pressure (RVP) in
monocrotaline-induced pulmonary hypertensive rat model
RVP (mmHg) SD
Negative control group
(monocrotaline non-administered 12.6 3.0
group)
Vehicle control group 30.4 3.5
1 mg/kg administration group 26.4 3.0
3 mg/kg administration group 22.4 5.0
mg/kg administration group 17.8 2.4
[0053]
The data in the table is indicated by mean
standard deviation.
[0054]
As shown in Table 1, compound A' remarkably improved
the right ventricular pressure at 28 days after MCT
administration.
[0055]
(3) Effect on right ventricular systolic pressure (RVSP)
The right ventricular systolic pressure (RVSP) was
measured by catheterization for the rats that survived at
28 days after MCT administration ((negative control group
(monocrotaline non-administered group), 9 rats; vehicle
control group, 8 rats; compound A' 1 mg/kg administration
group, 9 rats; compound A' 3 mg/kg administration group,
5 rats; compound A' 10 mg/kg administration group, 9
rats; total 40 rats)). The results are shown in Table 2.
[0056]
[Table 2]
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Effect on right ventricular systolic pressure (RVSP) in
monocrotaline-induced pulmonary hypertensive rat model
RVSP SD
(mmHg)
Negative control group 22.2 3.2
(monocrotaline non-administered
group)
Vehicle control group 56.5 4.7
1 mg/kg administration group 48.3 5.3
3 mg/kg administration group 39.1 2.9
mg/kg administration group 28.0 , 3.4
[0057]
The data in the table is indicated by mean
standard deviation.
[0058]
As shown in Table 2, compound A' remarkably improved
the right ventricular systolic pressure (RVSP) at 28 days
after MCT administration.
[0059]
(4) Effect on right ventricular hypertrophy
The right ventricle weight (RV), left ventricle
weight (LV), and interventricular septum weight (S) were
measured for pulmonary hypertensive rat models that
survived at 28 days after MCT administration (negative
control group (monocrotaline non-administered group), 9
rats; vehicle control group, 8 rats; compound A' 1 mg/kg
administration group, 9 rats; compound A' 3 mg/kg
administration group, 5 rats; compound A' 10 mg/kg
administration group, 9 rats; total 40 rats)), and RV/(LV
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+ S) was determined as an index for right cardiomegaly.
The results are shown in Table 3.
[0060]
[Table 3]
Effect on right ventricular hypertrophy in monocrotaline-
induced pulmonary hypertensive rat model
RV/(LV+S) SD
Negative control group
(monocrotaline non-administered 0.271 0.042
group)
Vehicle control group 0.452 0.108
1 mg/kg administration group 0.333 0.035
3 mg/kg administration group 0.307 0.062
mg/kg administration group 0.282 0.070
[0061]
The data in the table is indicated by mean
standard deviation.
[0062]
As shown in Table 3, compound A' remarkably improved
the right ventricular hypertrophy at 28 days after MCT
administration.
[0063]
(5) Effect on pulmonary artery medial wall thickening
Concerning the pulmonary hypertensive rat models
that survived at 28 days after NOT administration
(negative control group (monocrotaline non-administered
group), 9 rats; vehicle control group, 8 rats; compound
A' 10 mg/kg administration group, 9 rats), tissue
specimens of pulmonary tissue sections were prepared from
5 rats per group (total 15 rats) by Elastica van Gieson
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staining method to measure the thickening of the medial
wall of the pulmonary artery. The results are shown in
Table 4.
[0064]
[Table 4]
Effect on pulmonary artery medial wall thickening in
monocrotaline-induced pulmonary hypertensive rat model
Diameter of Diameter of
pulmonary artery pulmonary
artery
(<50 M) (50 M-100 M)
Thickness of Thickness of
pulmonary pulmonary
SE SE
artery artery
medial wall medial wall
Negative control
group
(monocrotaline 3.51 0.20 6.37 0.65
non-administered
group)
Vehicle control
5.94 0.35 12.34 0.98
group
mg/kg
administration 4.28 0.25 6.86 0.43
group
[0065]
The data in the table is indicated by mean
standard error.
[0066]
As shown in Table 4, compound A' remarkably improved
the thickening of the pulmonary artery medial wall at 28
days after MCT administration.
[0067]
(6) Effect on pulmonary artery occlusion
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Concerning the pulmonary hypertensive rat models
that survived at 28 days after MCT administration
(negative control group (monocrotaline non-administered
group), 9 rats; vehicle control group, 8 rats; compound
A' 10 mg/kg administration group, 9 rats), tissue
specimens of pulmonary tissue sections were prepared from
rats per group (total 15 rats) by Elastica van Gieson
staining method to measure occlusion of the pulmonary
artery. A value obtained by dividing a value that is
twice as much as the thickness of the pulmonary artery
medial wall by the diameter of the pulmonary artery was
used as an index of occlusion. The results are shown in
Table 5.
[0068]
[Table 5]
Effect on pulmonary artery occlusion in monocrotaline-
induced pulmonary hypertensive rat model
Diameter of Diameter of
pulmonary artery pulmonary artery
(<50 M) (50 RN-100 M)
Pulmonary Pulmonary
artery SE artery SE
occlusion , occlusion
Negative control
group
(monocrotaline 0.19 0.01 0.19 0.02
non-administered
group)
Vehicle control
0.28 0.02 0.32 0.02
group
mg/kg
administration 0.20 0.01 0.19 0.01
group
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[0069]
The data in the table is indicated by mean
standard error.
[0070]
As shown in Table 5, compound A' remarkably improved
occlusion of the pulmonary artery at 28 days after MCT
administration.
[0071]
Example 2: Therapeutic effect of compound A' on pulmonary
hypertension in pulmonary hypertensive animal model
(survival rate)
[0072]
(1) Experimental method
Monocrotaline (MCT) was subcutaneously injected at
50 mg/kg (in 50% dimethyl sulfoxide solution) to male
Sprague-Dawley rats having a body weight of 230 g 10 g
to prepare pulmonary hypertensive rat models. Compound
A' and the same amount of a vehicle were orally
administered to a compound A' administration group (dose:
1 mg/kg, 3 mg/kg, or 10 mg/kg) and a control group,
respectively, once every day over 14 days from the 14th
day after the NOT administration. This experiment was
carried out using these groups each involving 12 rats.
[0073]
(2) Effect on survival rate
Figure 1 shows a Kaplan-Meier survival curve
obtained from the above experiment.
CA 03019091 2018-09-26
4 P
- 33 -
[0074]
As shown in Figure 1, compound A' remarkably
improved the survival rate of animals after
administration.
[0075]
Example 3: Effect on CHP1-NHE1 interaction
[0076]
In addition to CaSR, NHE (Na+-H* exchange) protein is
shown to be an important molecule involved in the
pathology of pulmonary hypertension in experiments or the
like involving administration of various NHE inhibitory
compounds to animal models of pulmonary hypertension
induced by, for example, monocrotaline and hypoxia, as
well as NHE knockout animals (Chen et al., 2001; Huetsch
et al., 2016; Huetsch and Shimoda, 2015; Yu et al., 2008).
CHP is a cofactor essential to the localization of NHE in
a cell membrane and the function thereof (Matsushita et
al., 2007; Mishima et al., 2007; Pang et al., 2001).
Accordingly, whether compound A' inhibits the interaction
of NHE1-CHP1 was investigated.
[0077]
(1) Experimental method
The inhibitory activity of compound A' on the
interaction between human NHE1 and human CHP1 was
evaluated in a protein interaction measurement system
using an amplified luminescence proximity homogeneous
assay (AlphaScreenTM (PerkinElmer)). A microsomal
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- 34 -
fraction of FLAG-tagged full-length human NHE1 (Accession
No. NM 003047) was prepared by being expressed in human
_
embryonic kidney cell-derived FreeStyleTM 293 cells. Also,
biotinylated full-length human CHP1 (Accession No.
NM 007236) was expressed in a wheat germ cell-free
_
translation system and purified. The NHE1 microsomal
fraction and CHP 1 were diluted with an assay buffer (25
mM Tris-HC1 (pH 7.4), 137 mM NaC1, 2.7 mM KC1, 0.1% BSA,
1 mM DTT), and compound A' was added thereto. Then, the
mixture was added to an Alpha Plate-384 Shallow Well
(Perkin Elmer) in an amount of 2 L/well, and reacted at
room temperature for 60 minutes. Acceptor Beads and
Donor Beads accompanying an AlphaScreen FLAG(M2)
Detection Kit (PerkinElmer) were added thereto each in an
amount of 2 L/well, and the mixture was reacted at room
temperature for 60 minutes. Thereafter, the AlphaScreen
signal intensity was measured using an EnSpire Multi-
label reader (PerkinElmer). Different concentrations of
compound A' (concentration: 50.0 nM to 0.8 nM) were
evaluated in this test system.
[0078]
(2) Results
The results are shown in Table 6.
[0079]
[Table 6]
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- 35 -
Effect on CHP1-NHE1 interaction
Compound CHP1-NHE1 interaction activity (50%
inhibitory concentration)
Compound A' 4.7 nM
[0080]
As shown in Table 6, compound A' showed remarkable
CHP1-NHE1 inhibitory activity.
Industrial Applicability
[0081]
The present invention provides a medicament for
preventing or treating pulmonary hypertension and is thus
useful.
[0082]
The present application claims priority to Japanese
Patent Application No. 2016-063747 (filed on March 28,
2016).
Date Recue/Date Received 2023-03-15
